This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. From the standpoint of causing high morbidity and mortality, dengue fever, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) have emerged as the most important arthropod-borne viral diseases of humans worldwide. That these diseases are immune-mediated is undisputed, but insufficient knowledge about the T-cell responses following primary infection with a single dengue virus serotype has hampered a better understanding of the host determinants of disease severity. The objective of this research project is to determine the CD4+ and CD8+ T-lymphocyte responses in humans months to decades following primary dengue virus infection. The central hypothesis is that dengue virus serotypespecific memory T cells, upon stimulation with heterologous dengue virus antigens, release cytokines which contribute to the immunopathogenesis of DHF/DSS. The proposed five-year study will test our hypothesis by pursuing the following specific aims: 1. Determine the specificity and duration of dengue virus serotype 1-specific T-cell responses following primary infection, and assess T-cell reactivity following stimulation with heterologous dengue virus antigens. 2. Characterize the proinflammatory cytokine responses of dengue virus-specific T cells by flow cytometry. 3. Characterize the relationship between viremia, immune-activation markers, and T-cell responses following primary dengue virus infection. Serotype-specific T-cell responses and T-cell reactivity to heterologous dengue virus antigens will be studied in individuals infected during the dengue fever outbreak in Hawaii in 2001-2002, and those infected during the previous outbreak in 1945. This project is innovative because it will provide new knowledge about the specificity and duration of cell-mediated immune responses to primary infection with a single dengue virus serotype. Newfound knowledge from this project will have a significant impact on guiding vaccine development for dengue fever and DHF/DSS, particularly in the tropical Asia-Pacific region.